It is clear from many studies that HIV-1-specific CD8+ and CD4+ T cell responses have a prominent role in controlling viral replication (1-4). However, in most cases cellular immunity to HIV-1 proves incapable of long-term control of viremia, and without antiretroviral therapy, progression to AIDS occurs. It has become evident that the ultimate failure of the host immune system to contain HIV-1 is related to the functional impairment of virus-specific CD8+ and CD4+ T cells which accompanies progressive HIV-1 infection, a phenomenon referred to as T cell exhaustion (5-7).
Effective T cell responses are characterized by polyfunctional cytokine production, cytotoxic potential, and strong proliferation in response to antigen (11-14). In the context of chronic infection with HIV-1, the deterioration of the T cell response follows a characteristic pattern. Proliferative capacity, cytotoxic potential, and the ability to produce IL-2 are lost early, while production of IFN-γ is more enduring. Ultimately, the majority of both CD8+ and CD4+ T cells chronically exposed to antigen lose the ability to produce IFN-γ and enter into a state of peripheral anergy (8-13). This has been demonstrated by tetramer studies which have observed that only a small fraction of HIV-1-specific T cells produce cytokine in response to antigen (14-18). Recently, a step forward has been made in understanding T cell exhaustion by the identification of a causative contribution of signaling through PD-1 (5-7). Given the characteristic complexity of T cell regulation, other mechanisms for dampening effector functions of chronically activated cells likely exist.
T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) is an immunoglobulin (Ig) superfamily member. The murine homologue of Tim-3 was identified as a specific cell surface marker of Th1 CD4+ T cells (19). Interaction of murine Tim-3 with its interferon inducible ligand galectin-9, has been shown to regulate Th1 responses by promoting T cell aggregation and the death of IFN-γ producing Th1 cells (20). In mice, blockade of the Tim-3 pathway prevents the acquisition of transplantation tolerance induced by costimulatory blockade (21) (22). Furthermore, Tim-3-deficient mice are refractory to the induction of high dose tolerance in an experimental autoimmune encephalomyelitis (EAE) model, and anti-Tim-3 mAbs treatment of SJL/J mice exacerbated EAE (23) (19). Together, these results show that Tim-3 interactions play a role in suppressing Th1 mediated immune responses in mice through the termination of effector Th1 cells.